HIV/AIDS in Practice: Choosing a First Regimen, a Clinical Context Report

by Michael Smith Michael Smith North American Correspondent, MedPage Today
October 21, 2011

Transcript:

MICHAEL SMITH: I'm Michael Smith of MedPage Today, and I'm here today with Dr. Cal Cohen, who is Research Director of the Community Research Initiative of New England and also a clinician at Harvard Vanguard Medical Associates, and those are both in Boston. Dr. Cohen, welcome to MedPage.

CALVIN COHEN, MD: Thanks very much for having me.

SMITH: We're going to talk today a little bit, obviously just brushing the surface of this, about what medications are available to treat HIV and the kinds of choices that a clinician makes for initial therapy.

When we first met -- this was many years ago -- your organization, the Community Research Initiative, was handing out a laminated sheet that had all of the available drugs at the time and a little pile that showed how many pills you had to take.

COHEN: Um-hmm.

SMITH: And it was impressive because some people were taking, you know, 10, 20, 30 pills a day at different times.

COHEN: Sure, sure.

SMITH: It's safe to say times have changed.

COHEN: Times have changed, for the better.

SMITH: Let's talk then - we're going to talk a little bit about initial treatment of HIV. Subsequent treatment of treatment-experienced patients is very idiosyncratic; for initial treatment, though, there are guidelines. And the IAS-USA Panel guidelines suggest some initial regimens, and specifically they talk about certain types of drugs that you should use for the first thing, for the first treatment regimen. When a patient arrives in your office with HIV, not having been treated before, what do you choose? How do you go about choosing a regimen?

COHEN: Sure. Well, let me just give one moment to "Do we treat?", since obviously there's a decision to be made about when to treat; that's its own topic. It is fair to say that we have guidelines around that, and there are uncertainties as well as certainties.

But let's move on from we have decided to start treatment. The person's CD4 count is low enough; they are ready for treatment. They are ready to commit to treatment, which is a key factor.

So how do we choose our best regimens? Thankfully, our field has been doing a lot of randomized clinical trials for years. And on the basis of the accumulated wisdom from those trials, we currently have four regimens in our so-called preferred list. And the reason that they are preferred is that these are the regimens that have never come in second, they have never lost in a head-to-head contest of that regimen versus another one.

And so we have four to choose from. All of our regimens are based on three drugs. And for the two-nucleoside aspect of the three, the current standard of care is the choice of tenofovir plus emtricitabine, also known as FTC.

The reason those two are chosen in all of the regimens is because those two nucleosides combine the best sustained efficacy at any patient's viral load at any CD4 count, as well as the best trade-offs in terms of safety; people do well most, if not all, of the time. All of our medicines have potential toxicities, so all of these are looking at all of the different options and saying which ones have the best balance, and tenofovir/FTC, in the eyes of our panels, has the best balance of the best in terms of efficacy and the best in terms of safety.

SMITH: Okay.

COHEN: And then there's the third drug.

SMITH: Okay, let's stop just for a second, because there is another second -- second choice, if you will, for the NRTI [nucleotide reverse transcriptase inhibitors] backbone.

COHEN: Sure.

SMITH: And that's abacavir lamivudine.

COHEN: That's right.

SMITH: What would you choose -- I mean obviously you'd like to go with the tenofovir emtricitabine; yet, as you say, it's slightly better. But there may be circumstances in which you'd use the other.

COHEN: Sure.

SMITH: And what would those be?

COHEN: Well, probably the clearest reason one would need to avoid the use of tenofovir/FTC is a patient with compromised renal function at baseline. Tenofovir is renally cleared and if somebody has a creatinine clearance below 50, it would make using tenofovir perhaps cumbersome if not perhaps more risky, the reason being that tenofovir would at least need to be dosed every other day in somebody with severely compromised renal function and may in fact add to the renal dysfunction of that patient. So, as a result, in general, instead of going to every-other-day dosing, we'd much rather use an alternative, and abacavir/3TC probably represents the best choice.

The reason abacavir/3TC, however, is considered an alternative choice is really based on two things in our guidelines; one is that in a head-to-head trial, for people with high viral loads -- high being over 100,000 copies -- it did not do as well. It did not create virologic suppression as consistently as did tenofovir/FTC, so for that reason it was downgraded.

In addition, there are some safety concerns about abacavir specifically, and there are data to at least suggest that abacavir may be associated with a greater risk of myocardial infarcts through a mechanism that has some possible routes of how that might happen, though there's some uncertainty. Those data are conflicted. There are data sets that don't see this. There are data sets that do. Clinicians vary on how they feel about it. But nevertheless, we do have an alternative for people who need it.

SMITH: All right. Let's move to the third agent. There are -- the guidelines suggest, I think, four agents as a possibility.

COHEN: That's right.

SMITH: And in order. And we'll take them maybe in order. Efavirenz; atazanavir boosted with ritonavir; darunavir, a new drug, a relatively new drug -- again boosted with ritonavir; and raltegravir -- again, another new drug. Let's start with efavirenz; it's the most widely used of the third agents.

COHEN: Sure.

SMITH: Why is that?

COHEN: Well, there are a couple of reasons why; the first is implied in the way you list it. I mean this is the one for which we have the longest track record. We've got a decade of experience with efavirenz. Efavirenz was presented to us for the first time at the 1998 Geneva World AIDS Conference. And since then we have seen, in study after study, when efavirenz is given in a randomized trial of efavirenz versus something else, efavirenz has never come in second. In terms of efficacy, it has always been a standard of care in our field. And so for that obvious reason, it deserves to be on our list.

In addition, while there are some initial toxicities to it, on the other hand, most people -- though not all -- most people do in fact tolerate the drug if they can get through that first month. The first month does have its challenge, which is in part why we have alternatives. But the first month, about maybe 30, 40% will experience some toxicity, some side effects. Interesting enough, those toxicities may wane after a month, so a patient can often stick with it and see if they are in fact going to have a better second month than their first, and not everybody has a side effect. But nevertheless, efavirenz has an excellent track record of delivering on efficacy with an acceptable safety profile that makes it a very attractive drug to use.

There's one more feature: Tenofovir/FTC and efavirenz are available as a single tablet, and for that reason alone, clinicians and patients are often drawn to simplicity. And simplicity is an obvious plus for patients who have to be treated for decades, entire lives of treatment. A single tablet taken once at bedtime is pretty easy to do.

SMITH: Right. And, of course, the toxicities that are associated with it are well known at this point. So a clinician will say to a patient, you know, this could well give you a range of toxicities.

COHEN: Yes.

SMITH: Including bad dreams or exciting dreams.

COHEN: That's right.

SMITH: Somnolence, a range of neurological ...

COHEN: Exactly. No, it's not a -- certainly there's no need for surprises on a patient. And obviously our job is to say here's what you might expect, and then a patient will see what happens. For the most part, it is something that, with the right coaching, people can get through. But on the other hand, some people don't tolerate it well. And those toxicities you just mentioned, like the morning dizziness, like the abnormal dreaming, for some people are just too much and they would rather have an alternative, which is why it's great to have alternatives.

SMITH: And let's talk about those a little bit. Atazanavir; it's boosted with ritonavir.

COHEN: Yes.

SMITH: What can we say about that? Why would you choose that? I mean obviously the toxicity issue is a major one.

COHEN: Sure.

SMITH: But why would you go with that rather than, say, with one of the other three?

COHEN: Well, so let's start at the beginning with efficacy. In the head-to-head trial of efavirenz versus boosted atazanavir, they are tied, so there's no trade-off in terms of any difference in terms of overall efficacy. In our studies, they are spot-on in terms of how well each of them performs.

So we go to boosted atazanavir because it is, first of all, a pretty simple regimen; we're talking about three pills once a day with something to eat. And it doesn't have the toxicities, the CNS toxicities, associated with efavirenz.

It does have one or two signature issues that require us to at least, again, share this with our patients. The first is that its signature toxicity is in some patients they might have an increase in their bilirubin that results in either scleral icterus or actual jaundice. Now, this is not a liver toxicity; this is a change in the processing of bilirubin. So what happens is that the indirect bilirubin builds up in terms of, like, a condition, like Gilbert's. Patients might notice a little bit more yellow tint to their skin or their eyes. Again, we'd certainly reinforce with our patients this is not a toxicity, this is not harm to your liver, this is simply a change in bilirubin processing. We can monitor their bilirubins, but, in all honesty, I don't think there's any purpose to checking the lab test. If a clinician doesn't see it, if the patient doesn't notice it in their skin, what it is in terms of blood test is medically unimportant; it's a cosmetic issue.

SMITH: Right.

COHEN: So that's one thing that we have to disclose to our patients. The other is that it requires acid for absorption, and as we know, proton-pump inhibitor use is widespread, and unfortunately over the counter. I say "unfortunate" because it makes it harder for us to ensure that a patient won't be on a PPI if they're on atazanavir. There are ways to co-dose by dose separation in time. Nevertheless, it is ... part of our job is to make sure the patients understand this drug has a certain drug interaction and that for patients with a history of heartburn, maybe atazanavir isn't the right drug for them.

SMITH: Right. The third drug on our little list is darunavir, again boosted with ritonavir; that's a relatively new protease inhibitor. Again, you might choose that for some reason or other. What would those be?

COHEN: Sure. So, well, relatively new first -- let's say that the drug's been around for probably a decade, so then we've got years of experience with it, so relatively new means three to four years of FDA approval as opposed to a decade.

SMITH: Right.

COHEN: So we certainly don't feel like we're still getting to know [it]; we know this drug. Why would we use it? Well, like atazanavir, ritonavir-boosted protease inhibitors have an extraordinary property, which is that in addition to high rates of virologic suppression, in patients who are erratic in their dosing, who miss doses, in which the virus might escape and return, boosted protease inhibitors have what we call a genetic barrier to resistance, meaning that it's very hard for the virus to create resistance to the protease inhibitor. And so for that reason alone, there are clinicians who are very attracted to protease inhibitors, either one of the two we mentioned, because in the patients who succeed, they're fine, but in the patients who are erratic in dosing and they are viremic, we can count that the protease inhibitor will maintain its ongoing activity; that we won't lose it to resistance, which is not the case with efavirenz. People can lose efavirenz if they are too erratic in their dosing.

So darunavir is a great drug. It's a consistent drug. It doesn't have the jaundice of atazanavir. It doesn't have the proton-pump interaction of atazanavir. It is one more tablet than atazanavir, so we're talking about a regimen of four pills once a day with something to eat instead of three.

And so from a patient perspective, if I don't have heartburn, I could take one pill, I could take three, I could take four. And for a patient, why would I take four if I can take fewer? Oftentimes, it's really as simple as that. The good news is that the companies continue to try to co-formulate, reformulate, to reduce the pill burden.

Darunavir is great. It has few if any signature toxicities. It's probably -- its burden, if you will, is that it has one more pill, and for some patients that's just one pill too many.

SMITH: Right. Just slightly less convenient.

COHEN: Yes, just slightly.

SMITH: The final drug in that list is raltegravir, and that's a different class entirely, a new class; that's the integrase inhibitors.

COHEN: Yes.

SMITH: And it's the only one approved in that class as yet. Why would you go with that, that entirely different mechanism of action from the ones we've talked about so far?

COHEN: Sure, absolutely. Well, so let's briefly mention that we've got three different mechanisms of actions for this third drug: We have the non-nucleoside, efavirenz; the protease inhibitor for the atazanavir, darunavir; and now the integrase inhibitor. We haven't really talked much about mechanism of action, and in all honesty I'm not sure we need to, meaning how it suppresses the virus is relatively unimportant to the fact that it does, and it does so reliably. So the drug characteristics are way more important rather than how it accomplishes this.

So we've got the integrase inhibitor, raltegravir. What's impressive about raltegravir is that in head-to-head trials of placebo versus raltegravir in the studies that had a background regimen, raltegravir had placebo-like adverse event rates. It was hard to distinguish from a placebo ...

SMITH: So they're very safe and tolerable, then.

COHEN: Extraordinary, right, and that continues to be the case. Not that there are no toxicities; the few patients might have had elevated CPKs [creatine phosphokinase]. There are some case reports of some people who noticed some minor CNS [central nervous system] disturbances, of feeling irritable, but we're at the level of case reports. So it otherwise has this 99% track record of ongoing safety. It is also a very durable regimen, and it's terrific in terms of those characteristics. It is also as potent as efavirenz, so it's as good as our standard of care.

Its burden, if you will, its downside, is that it needs to be dosed as one pill twice a day, not once a day. Some patients can do twice a day no problem, but some can't, some will miss a dose, and because of that, we unfortunately did a study of once-a-day versus twice-a-day, and I say "unfortunate" because while once-a-day raltegravir did great, it didn't do as well as twice a day. And so when we want to use raltegravir, we would prefer to use it twice a day to get the best possible efficacy out of the drug; again, there are patients in whom twice a day is not a problem. "I'm taking other medicines. I take something in the morning. At night I have no problem with it." But there are a subset of our patients for whom twice a day is just hard to remember and missing a dose compromises efficacies.

SMITH: Right. Now, there are, of course -- those are sort of the top drugs. There are many others, some that are not widely used in the United States that are widely used elsewhere. There are some that are hardly used at all; things like didanosine.

COHEN: Um-hmm.

SMITH: Sort of have fallen out of favor. And there are other potential first-line agents: The protease inhibitor lopinavir, fosamprenavir. And of course, another class: The entry inhibitors, maraviroc; and I think we can probably class enfuvirtide in there as well.

COHEN: Sure.

SMITH: Enfuvirtide is an injectable, so that's hard for a lot of people to take.

COHEN: Exactly.

SMITH: The others are all oral. Again, are there circumstances in which you would sort of say, "Oh, I've got to go for one of those -- lopinavir, maraviroc, fosamprenavir?"

COHEN: Well, while one could create scenarios in which these other alternatives make sense, I think that right now our focus is the fact that one of these four probably fits almost all of our naive patients, but are there circumstances in which we might prefer an alternative? We've already mentioned that in terms of the tenofovir/FTC part, the patients with renal compromise, we are looking for an alternative.

In terms of an alternative to efavirenz, for example, efavirenz is considered a teratogenicity risk. And so for a woman who is considering pregnancy and in whom pregnancy might happen in an unplanned way, efavirenz is not the right choice. One of the other three drugs we talked about might be, but on the other hand, there are patients who don't tolerate ritonavir. And if somebody doesn't tolerate ritonavir, if they feel kind of a GI toxicity, which is the most common, then either ritonavir/atazanavir or ritonavir/darunavir, won't be the right choice for them. And if they tell us that the twice-daily raltegravir is hard to remember, then there goes all four.

So yes, it is good to have a portfolio of options. We just had the FDA approval of our second single-tablet option which uses a novel non-nucleoside called rilpivirine. And again, our guidelines consider it an alternative to the top four, but again, it's not too hard to get to a scenario where rilpivirine will at least come up in the conversation; for example, it got a Category B from the FDA. And so if a woman is considering pregnancy and would prefer a single tablet, efavirenz is not the right choice for her, whereas rilpivirine might be a preferred choice for her.

SMITH: Right. And we haven't discussed that in detail because, of course, it's very, very new; it's just been approved earlier this year.

COHEN: Absolutely.

SMITH: Dr. Cohen, I think we could probably go for some hours, but we won't. Thank you very much for your insights; very clear and very detailed.

So, in summary, at the end of this activity, participants should understand:

The recommended and alternative pairs of NRTIs that form the backbone of a regimen for most treatment-naive patients

Potential toxicities and other factors that might influence the choice of NRTI backbone

Benefits, such as ease of compliance, that might influence the choice

The four recommended key third agents and their classes

Potential toxicities and other factors that might influence the choice of a key third agent

Other key third agents that are available as alternatives

The elements of the two available single-pill triple-drug combinations

More in Clinical Context

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.